The innate immune system detects viral infection primarily by recognizing viral nucleic acids inside an infected cell. In the case of retroviruses, which are RNA viruses that replicate via a DNA intermediate, the reverse transcribed DNA is believed to be recognized during entry into a host cell by a cytoplasmic DNA sensor(s) that triggers type I IFN production. This latter response has been observed in cells that lack the endoplasmic reticulum (ER)-associated 3′->5′ exonuclease, TREX1. When TREX1 is present, it can degrade the viral DNA before sensing occurs.
A similar fate appears to be the case with self DNA from the host cell, as deficiency in TREX1 leads to the accumulation of endogenous retroelements and genomic DNA in the cytoplasm, causing aberrant over-activation of the DNA-sensing pathway and subsequent initiation of autoimmune disease. Currently treatments target the symptoms of such autoimmune diseases. Accordingly, there is a need for a more complete understanding of the DNA sensing pathway to develop targeted treatments.
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